1. Field of the Invention
The invention relates to the province of antitumor agents. In the present description the expression "antitumor agents" is synonymous with the expression "cytostatic agents". The subject of the present invention is an improved form of presentation of such agents which enables them to be endowed with increased efficiency. The invention also relates to the preparation of new forms of presentation of the agents in question and, in general, a process for increasing the efficiency of use of antitumor agents or cytostatic agents.
2. Description of the Prior Art
It is known that the use of present antitumor agents raises many difficulties in practice. At doses which are high enough to be effective, such agents are extremely toxic. Their use is however justified by the seriousness of the illnesses which have to be combated. Furthermore, clinical treatment conditions are themselves far from being optimal because, in many cases, the active agents are very rapidly eliminated from the organism, so that they have to be administered more frequently, which further increases the toxicity hazards and, in any case, makes the treatment very uncomfortable for the patient.
In recent work, various attempts have been made to overcome these disadvantages, in particular by fixing the antitumor agent, for example daunomycin (or daunorubicin) on various soluble or insoluble supports. There may be mentioned in this connection the paper by A. Bernstein et al., J. Natl. Cancer Inst. 1978, 60, 379-384. The authors propose to fix daunomycin on dextran to improve antitumor efficiency. For the purpose of fixing, dextran, which is previously oxidized, is brought together with daunomycin and the combination is then reduced with sodium borohydride. The authors report a number of undesirable secondary effects at the time of the administration, as a result of the presence of the dextran as a supporting agent.
There may also be mentioned as a literature reference the paper by E. Hurwitz, M. Wilchek and J. Pitha, Soluble Macromolecules as Carriers for Daunorubicin., J. Appl. Biochem. 2,25-35 (1980). According to these authors, daunorubicin is fixed through its ketone group on soluble macromolecular hydrazides, in a reversible manner. The fixation takes place, consequently, by means of sulfide bonds. The difficulties which are met with are that the product no longer possesses its cytotoxic properties, or that the conjugated agent gradually becomes insoluble, which makes it unsuitable for administration.
The paper by Sjur Olsnes "Directing Toxins to Cancer Cells" in Nature, Vol. 290, Mar. 12, 1981, gives a good description of the problems involved in the administration of antitumor agents having very high toxicity. It refers to a number of techniques for trying to improve the conditions of administration, and in particular to permit a more direct action of the active agent on the cancerous cell by improving its selectivity. It is proposed, for example, to fix the antitumor agent on a toxin capable of acting directly on the cell.
There may also be mentioned the paper by Jung-Yaw Lin, Jiann-Shyong Li and Ta-Cheng Tung "Lectin Derivatives of Methotrexate and Chlorambucil as Chemotherapeutic Agents", JNCI, Vol. 66, No. 3, March 1981. The authors propose to fix the agents, by covalent bonding, on a lectin, so as to prepare a conjugated product whose efficiency is superior to the active agent employed separately.
In general, various processes are known, especially in recent years, which are intended for conveying the medications, retarding their elimination, reducing their toxicity, and, particularly, increasing their activity. These studies are, among others, the subject of a recent publication: Drug Carriers in Biology and Medicine, G. Gregoriadis (ed.) Academic Press 1979, which summarizes the results obtained with natural macromolecules, cells and synthetic compounds (such as the liposomes).
Other ways which have been the subject of recent publications are: arterial chemoembolization with microcapsules containing an anticancer agent (T. Kato et al., JAMA 1981, 245, 1123-1127), antibody carriers for toxins or anticancer agents (H. E. Blythman et al., NATURE 1981, 290, 145-146; S. Olsnes, NATURE 1981, 290, 84; E. Hurwitz et al., Europ. J. Cancer 1978, 14, 1213-1220), the use of implantable pumps (JAMA 1981, 246, 925-926).
The problems posed by the administration of antitumor agents or cytostatic agents are made particularly difficult by the nature of the illness and very high toxicity of the active product. The aim of the invention is generally to improve the efficiency of the use of antitumor agents, so as to allow their gradual release in the organism, which clearly improves their efficiency and the patient's comfort.